Pediatric Hypertension
Conditions
Brief summary
The single patient (n-of-1) randomized trial is an underused approach to resolving therapeutic uncertainty by using a patient's own data to inform an individualized treatment plan. The proposed research is designed to assess whether the n-of-1 trial approach improves blood pressure control compared to usual care. This trial aims to advance learning about not only the treatment of pediatric hypertension but also the use of a neglected type of randomized trial to optimize the care of each patient.
Detailed description
Pediatric hypertension, a growing problem, often requires prescription of antihypertensive medication. Pediatric hypertension specialists lack an evidentiary base on which to establish definitive clinical practice guidelines for first-line therapy. Significant practice variation is an unsurprising consequence. Routine choice of the same first-line therapy for most patients with hypertension, absent testing other options, may delay correction of blood pressure for months or years. Failure to incorporate patient preferences in medical decision-making may also contribute to decreased patient satisfaction and adherence. Large parallel-group, comparative effectiveness trials are likely not on the horizon for this population. Moreover, heterogeneity of treatment effects would minimize the generalizability of such a trial to all patients. This is a parallel-group, randomized clinical trial to compare the n-of-1 trial approach to usual care in normalizing blood pressure while minimizing exposure to compliance-reducing side effects.
Interventions
OTHERUsual care
Physician preference will dictate choice and adjustment of antihypertensive medication, BP measurement modality, interval between visits, and assessment of side effects.
DRUGAmlodipine
Calcium-channel blocker; antihypertensive
DRUGLisinopril
Angiotensin-converting-enzyme (ACE) inhibitor; antihypertensive
OTHERNICHE method
Based on underlying comorbidities at enrollment, patients will be assigned to either an unrestricted protocol (amlodipine versus lisinopril) or a restricted protocol (losartan versus lisinopril). Two drugs are tested in randomized order. Failure to achieve BP control at maximum doses of the first two drugs will result in augmentation with a diuretic (hydrochlorothiazide). BP control is assessed with 24 hour ambulatory monitoring at the end of each 2 week treatment period. Side effect tolerability is assessed with a questionnaire.
DRUGHydrochlorothiazide
Thiazide diuretic; antihypertensive
DRUGLosartan
Angiotensin II receptor blocker (ARB); antihypertensive
Sponsors
National Center for Advancing Translational Sciences (NCATS)
The University of Texas Health Science Center, Houston
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
10 Years to 22 Years
Healthy volunteers
No
Inclusion criteria
* treating physician determines that pharmacologic therapy is indicated for treatment of hypertension * ambulatory hypertension has been confirmed (off meds) within 12 months of enrollment
Exclusion criteria
* age \< 10 years * resistant hypertension (requiring ≥ 3 drug therapy) * absolute contraindication or allergy to any of the tested drugs.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Ambulatory Blood Pressure (BP) Control at 6 Months | 6 months from enrollment | Blood pressure control is when ambulatory blood pressure is normal, with normal as defined by the American Heart Association (AHA) criteria \[the AHA criteria are systolic blood pressure and diastolic blood pressure (throughout wake and sleep) less than the 95th percentile based on the patient's gender and height\]. To assess ambulatory blood pressure, participants wear a 24-hour blood pressure monitor, which records blood pressure at regular intervals throughout a 24-hour period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mean 24-hour Ambulatory Systolic Blood Pressure | baseline, 6 months | To assess 24-hour mean ambulatory blood pressure, participants wear a 24-hour blood pressure monitor, which records blood pressure at regular intervals throughout a 24-hour period, while awake and while asleep. The mean of all recordings over the 24-hour period is calculated per participant for both baseline and 6 months, and then the mean 24-hour systolic blood pressure at 6 months minus the mean 24-hour systolic blood pressure at baseline is calculated per participant. The average difference is reported, with a negative value indicating a reduction in blood pressure over time. |
| Change in Mean Wake Ambulatory Systolic Blood Pressure | baseline, 6 months | To assess mean wake ambulatory blood pressure, participants wear a 24-hour blood pressure monitor, which records blood pressure at regular intervals throughout a 24 hour period, throughout wake and sleep. The mean of all recordings that occur while the participant is awake during the 24-hour period is calculated for both baseline and 6 months, and then the mean wake systolic blood pressure at 6 months minus the mean wake systolic blood pressure at baseline is calculated per participant. The average difference is reported, with a negative value indicating a reduction in blood pressure over time. |
| Number of Participants Who Reported That Side Effects From Medication Led Them to Discontinue Medication | from baseline to 6 months | — |
| Number of Participants Who Self-reported Adherence to Intervention | from month 5 to month 6 | Adherence is reported as the number of participants who self-reported at the 6-month visit that they had not missed any doses of their medication in the preceding month. |
| Patient Satisfaction With Intervention as Assessed by a Survey | 6 months | Patient satisfaction is scored from 0 to 10, where 0 is the worst health care possible and 10 is the best health care possible. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| NICHE Method In the NICHE method, antihypertensive therapy will be chosen using an n-of-1 trial to identify the preferred therapy. Preferred therapy is defined a priori as that which produces the greatest reduction in ambulatory BP without intolerable side effects. Tested drugs will include amlodipine or losartan, lisinopril, and hydrochlorothiazide.
NICHE method: Based on underlying comorbidities at enrollment, patients will be assigned to either an unrestricted protocol (amlodipine versus lisinopril) or a restricted protocol (losartan versus lisinopril). Two drugs are tested in randomized order. Failure to achieve BP control at maximum doses of the first two drugs will result in augmentation with a diuretic (hydrochlorothiazide). BP control is assessed with 24 hour ambulatory monitoring at the end of each 2 week treatment period. Side effect tolerability is assessed with a questionnaire.
Amlodipine: Calcium-channel blocker; antihypertensive
Lisinopril: Angiotensin-converting-enzyme (ACE) inhibitor; antihypertensive
Hydrochlorothiazide: Thiazide diuretic; antihypertensive
Losartan: Angiotensin II receptor blocker (ARB); antihypertensive | 23 |
| Usual Care No protocol will be introduced to standardize BP management in the control arm.
Usual care: Physician preference will dictate choice and adjustment of antihypertensive medication, BP measurement modality, interval between visits, and assessment of side effects. | 26 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | Total | NICHE Method | Usual Care |
|---|---|---|---|
| Age, Continuous | 15.9 years | 15.9 years | 15.9 years |
| BMI categories Health weight | 10 Participants | 4 Participants | 6 Participants |
| BMI categories Obese | 27 Participants | 13 Participants | 14 Participants |
| BMI categories Overweight | 12 Participants | 6 Participants | 6 Participants |
| BMI categories Underweight | 0 Participants | 0 Participants | 0 Participants |
| BMI percentile for gender and age | 96 percentile | 96.8 percentile | 95.8 percentile |
| Clinic Site County based clinic | 23 Participants | 11 Participants | 12 Participants |
| Clinic Site Multidisciplinary HTN clinic | 26 Participants | 12 Participants | 14 Participants |
| Hypertension type Primary | 39 Participants | 17 Participants | 22 Participants |
| Hypertension type Secondary | 10 Participants | 6 Participants | 4 Participants |
| Mean 24-hour ambulatory blood pressure at baseline (without medication) Diastolic blood pressure | 76 mm Hg | 76 mm Hg | 76 mm Hg |
| Mean 24-hour ambulatory blood pressure at baseline (without medication) Systolic blood pressure | 130 mm Hg | 130 mm Hg | 130 mm Hg |
| Number of participants who avoid calcium channel blocker | 1 Participants | 0 Participants | 1 Participants |
| Number of participants with Chronic Kidney Disease | 8 Participants | 5 Participants | 3 Participants |
| Number of participants with Diabetes Mellitus | 4 Participants | 2 Participants | 2 Participants |
| Number of participants with Proteinuria | 5 Participants | 2 Participants | 3 Participants |
| Primary language of parent English | 24 Participants | 11 Participants | 13 Participants |
| Primary language of parent Spanish | 25 Participants | 12 Participants | 13 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black (non-Hispanic) | 11 Participants | 5 Participants | 6 Participants |
| Race/Ethnicity, Customized Hispanic (black or white) | 35 Participants | 17 Participants | 18 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White (non-Hispanic) | 2 Participants | 1 Participants | 1 Participants |
| Region of Enrollment United States | 49 participants | 23 participants | 26 participants |
| Sex: Female, Male Female | 16 Participants | 9 Participants | 7 Participants |
| Sex: Female, Male Male | 33 Participants | 14 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 23 | 0 / 26 |
| other Total, other adverse events | 0 / 23 | 3 / 26 |
| serious Total, serious adverse events | 0 / 23 | 0 / 26 |
Outcome results
Primary
Number of Participants With Ambulatory Blood Pressure (BP) Control at 6 Months
Blood pressure control is when ambulatory blood pressure is normal, with normal as defined by the American Heart Association (AHA) criteria \[the AHA criteria are systolic blood pressure and diastolic blood pressure (throughout wake and sleep) less than the 95th percentile based on the patient's gender and height\]. To assess ambulatory blood pressure, participants wear a 24-hour blood pressure monitor, which records blood pressure at regular intervals throughout a 24-hour period.
Time frame: 6 months from enrollment
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| NICHE Method | Number of Participants With Ambulatory Blood Pressure (BP) Control at 6 Months | Controlled | 8 Participants |
| NICHE Method | Number of Participants With Ambulatory Blood Pressure (BP) Control at 6 Months | Uncontrolled | 10 Participants |
| Usual Care | Number of Participants With Ambulatory Blood Pressure (BP) Control at 6 Months | Controlled | 8 Participants |
| Usual Care | Number of Participants With Ambulatory Blood Pressure (BP) Control at 6 Months | Uncontrolled | 15 Participants |
Secondary
Change in Mean 24-hour Ambulatory Systolic Blood Pressure
To assess 24-hour mean ambulatory blood pressure, participants wear a 24-hour blood pressure monitor, which records blood pressure at regular intervals throughout a 24-hour period, while awake and while asleep. The mean of all recordings over the 24-hour period is calculated per participant for both baseline and 6 months, and then the mean 24-hour systolic blood pressure at 6 months minus the mean 24-hour systolic blood pressure at baseline is calculated per participant. The average difference is reported, with a negative value indicating a reduction in blood pressure over time.
Time frame: baseline, 6 months
Population: One patient in each arm was missing a baseline ambulatory blood pressure monitoring (ABPM), so change from baseline could not be calculated for each of those participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NICHE Method | Change in Mean 24-hour Ambulatory Systolic Blood Pressure | -10.6 mmHg | Standard Deviation 9.301 |
| Usual Care | Change in Mean 24-hour Ambulatory Systolic Blood Pressure | -5.1 mmHg | Standard Deviation 9.586 |
Secondary
Change in Mean Wake Ambulatory Systolic Blood Pressure
To assess mean wake ambulatory blood pressure, participants wear a 24-hour blood pressure monitor, which records blood pressure at regular intervals throughout a 24 hour period, throughout wake and sleep. The mean of all recordings that occur while the participant is awake during the 24-hour period is calculated for both baseline and 6 months, and then the mean wake systolic blood pressure at 6 months minus the mean wake systolic blood pressure at baseline is calculated per participant. The average difference is reported, with a negative value indicating a reduction in blood pressure over time.
Time frame: baseline, 6 months
Population: One patient in each arm was missing a baseline ambulatory blood pressure monitoring (ABPM), so change from baseline could not be calculated for each of those participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NICHE Method | Change in Mean Wake Ambulatory Systolic Blood Pressure | -10.5 mmHg | Standard Deviation 7.747 |
| Usual Care | Change in Mean Wake Ambulatory Systolic Blood Pressure | -6.2 mmHg | Standard Deviation 10.123 |
Secondary
Number of Participants Who Reported That Side Effects From Medication Led Them to Discontinue Medication
Time frame: from baseline to 6 months
Population: Data were not collected from 5 participants in the NICHE method arm, and data were not collected from 5 participants in the Usual Care arm
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NICHE Method | Number of Participants Who Reported That Side Effects From Medication Led Them to Discontinue Medication | 0 Participants |
| Usual Care | Number of Participants Who Reported That Side Effects From Medication Led Them to Discontinue Medication | 3 Participants |
Secondary
Number of Participants Who Self-reported Adherence to Intervention
Adherence is reported as the number of participants who self-reported at the 6-month visit that they had not missed any doses of their medication in the preceding month.
Time frame: from month 5 to month 6
Population: Data were not collected for 3 participants in the NICHE method arm.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NICHE Method | Number of Participants Who Self-reported Adherence to Intervention | 5 Participants |
| Usual Care | Number of Participants Who Self-reported Adherence to Intervention | 6 Participants |
Secondary
Patient Satisfaction With Intervention as Assessed by a Survey
Patient satisfaction is scored from 0 to 10, where 0 is the worst health care possible and 10 is the best health care possible.
Time frame: 6 months
Population: Data were not collected for 4 participants in the NICHE method arm. Data were not collected for 2 participants in the Usual Care arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NICHE Method | Patient Satisfaction With Intervention as Assessed by a Survey | 9.929 score on a scale | Standard Deviation 0.267 |
| Usual Care | Patient Satisfaction With Intervention as Assessed by a Survey | 9.667 score on a scale | Standard Deviation 0.73 |